Back to Search
Start Over
Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase
- Source :
- Breast Cancer Research : BCR
- Publication Year :
- 2014
-
Abstract
- Introduction Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance. Methods Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy. Results Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression. Conclusions Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0430-x) contains supplementary material, which is available to authorized users.
- Subjects :
- Cancer Research
Gene Expression
Mitogen-activated protein kinase kinase
Mitogen-Activated Protein Kinase
Phosphatidylinositol 3-Kinases
MCF-7 Cell
Sirolimu
ASK1
Molecular Targeted Therapy
Fulvestrant
Medicine(all)
TOR Serine-Threonine Kinase
biology
Estradiol
TOR Serine-Threonine Kinases
3. Good health
Editorial
Oncology
Receptors, Estrogen
Doxycycline
Gene Knockdown Techniques
MCF-7 Cells
Female
Mitogen-Activated Protein Kinases
Breast Neoplasm
Research Article
Human
Signal Transduction
Xenograft Model Antitumor Assay
Neoplasms, Hormone-Dependent
Antineoplastic Agents, Hormonal
Protein Kinase Inhibitor
Mice, Nude
Breast Neoplasms
PTEN
Animals
Humans
c-Raf
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Sirolimus
Animal
Cyclin-dependent kinase 4
Akt/PKB signaling pathway
PTEN Phosphohydrolase
Xenograft Model Antitumor Assays
Tamoxifen
Drug Resistance, Neoplasm
Gene Knockdown Technique
biology.protein
Cancer research
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 1465542X
- Volume :
- 16
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Breast cancer research : BCR
- Accession number :
- edsair.doi.dedup.....49b8e05d376b25b5859d608cc00f5d0f